Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson's disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin
Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson's disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin
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DOI：
10.1038/s41401-020-0379-5
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发表时间：
2020-02-28
影响因子：
8.2
通讯作者：
Zhen, Xue-chu
中科院分区：
文献类型：
--
作者：
Guo, Chen-hong;Cao, Ting;Zhen, Xue-chu
帕金森病（PD）是一种常见的神经退行性疾病，以运动功能障碍和多巴胺（DA）神经元的进行性丢失为特征。目前，常用1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）和6-羟基多巴胺（6-OHDA）等神经毒性药物急性应用来模拟PD的病理过程，但这些模型难以诱导PD的进展性发病过程。在这项研究中，我们采用DAT启动子介导的Cre转基因小鼠建立他莫昔芬诱导的Dicer条件性基因敲除（cKO）小鼠，努力模仿DA神经元的进行性丢失和PD样行为表型的发展。结果表明，Dicer cKO小鼠在他莫昔芬给药后表现出黑质（SN）中DA神经元的进行性丢失。在他莫昔芬给药后6周观察到显著的DA损失;相应地，还观察到进行性运动功能损害。我们还发现，一个显着的神经炎症反应，证明了小胶质细胞增殖，PD发病机制的另一个标志，伴随着DA神经元的损失。急性应用左旋多巴（l-DOPA）可减轻Dicer cKO小鼠PD样运动障碍，发挥其抗帕金森病作用，表明该模型可用于评价PD药物的抗帕金森病疗效。为了进一步阐明这种新型PD动物模型在PD药物开发中的潜在应用，我们采用了强大的神经保护剂二氢杨梅素（DHM）（10 mg/kg）和选择性σ-1受体激动剂PRE-084（1 mg/kg），这两种药物先前均显示出抗帕金森病作用。结果表明，DHM或PRE-084的长期给药减弱了Dicer cKO诱导的DA神经元损失和运动障碍，尽管这两种药物通过不同的机制起作用。这些数据表明，Dicer cKO小鼠模型可能是研究PD病理发展和干预介导变化的有用模型。总之，这种转基因小鼠模型似乎模拟了PD的渐进性发病机制，并可能成为PD药物发现的潜在有用模型。
Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor impairment and progressive loss of dopamine (DA) neurons. At present, the acute application of neurotoxic drugs such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are commonly used to simulate the pathology of PD; however, it is difficult to induce the progressive pathogenesis of PD with these models. In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes. The results showed that Dicer cKO mice exhibited progressive loss of DA neurons in the substantia nigra (SN) following tamoxifen administration. Significant DA loss was observed 6 weeks after tamoxifen administration; accordingly, progressive motor function impairment was also observed. We also found that a significant neuroinflammatory response, as evidenced by microglial proliferation, another hallmark of PD pathogenesis, accompanied the loss of DA neurons. The acute application of levo-DOPA (l-DOPA) relieved the PD-like motor impairments in Dicer cKO mice to exert its antiparkinsonian action, indicating that the model can be used to evaluate the antiparkinsonian efficacy of PD drugs. To further elucidate the potential application of this novel PD animal model for PD drug development, we employed the powerful neuroprotective agent dihydromyricetin (DHM) (10 mg/kg) and the selective sigma-1 receptor agonist PRE-084 (1 mg/kg), both of which were previously shown to produce antiparkinsonian effects. The results indicated that the chronic administration of either DHM or PRE-084 attenuated the Dicer cKO-induced loss of DA neurons and motor impairments, although the two drugs acted through different mechanisms. These data indicate that the Dicer cKO mouse model may be a useful model for investigating the pathological development of PD and intervention-mediated changes. In conclusion, this transgenic mouse model appears to simulate the progressive pathogenesis of PD and may be a potentially useful model for PD drug discovery.